發(fā)布時間：2018-05-17 00:39

  本文選題：內(nèi)皮素受體拮抗劑 + 波生坦　； 參考：《山東大學(xué)》2014年碩士論文

【摘要】：研究背景： 肺動脈高壓作為先天性心臟病(左向右分流型)常見的、嚴重的并發(fā)癥,它嚴重威脅著患兒的生命,患有嚴重肺動脈高壓患兒行手術(shù)治療的危險性及死亡率顯著增加,目前臨床尚缺乏特效的治療方法。因此,對肺動脈高壓的治療方法進行深入研究非常必要。 研究證明內(nèi)皮素-1(Endothelin-1,ET-1)為目前所被發(fā)現(xiàn)的、作用最強的縮血管物質(zhì),近年來發(fā)現(xiàn)ET-1不但為一種強效縮血管肽(血管內(nèi)皮細胞釋放的),同時亦是促血管平滑肌細胞(SMC)有絲分裂原。ET-1作為一種強力的內(nèi)源性血管收縮劑和致絲裂素,參與了多種心血管疾病的病理生理過程,也是先天性心臟病患者發(fā)生PAH的重要原因之一,因此抑制內(nèi)皮素-1具有控制PAH的作用。近年來研究發(fā)現(xiàn),左向右分流型先天性心臟病(先心病)肺動脈高壓患者血漿內(nèi)皮素-1水平升高,應(yīng)用DNA-RNA原位雜交法發(fā)現(xiàn)肺動脈高壓患者肺組織ET-1mRNA含量明顯增高[2]。目前認為ET-1導(dǎo)致肺動脈高壓形成的可能機制：ET-1與平滑肌細胞表面的內(nèi)皮素受體A(ETA)和B(ETB)結(jié)合,可引起肺動脈收縮、同時可促進肺動脈中層SMC的增生、分泌膠原等細胞外間質(zhì)增多,從而導(dǎo)致肺動脈管壁增厚,管腔狹窄,肺動脈高壓形成。而ET-1受體拮抗劑既可拮抗ET-1發(fā)揮的促肺動脈SMC增殖、肥大作用,又能拮抗ET-1的致缺氧性肺動脈高壓大鼠肺血管收縮及血管平滑肌細胞增殖作用。 波生坦是第一個獲得批準用于PAH的口服治療藥物,波生坦治療兒童PAH的非對照的開放式BREATHE-3研究首次證實,波生坦可安全應(yīng)用于兒童PAH的治療,明顯改善兒童PAH患者的血流動力學(xué)參數(shù)。2009年7月,波生坦在2歲以上的兒童PAH患者中的應(yīng)用得到了EMA的許可,推薦的初始劑量為2mg/kg bid。目前正在開展的FUTURE-3研究旨在評價3個月至12歲的兒童PAH患者每日服用2次與每日服用3次波生坦的藥代動力學(xué)、耐受性、安全性和療效,初步結(jié)果令人鼓舞。 波生坦最常見的副作用是轉(zhuǎn)氨酶升高,主要是因為該藥競爭性抑制膽鹽運輸所致,但是至今尚無永久性肝功能損害的報道。波生坦上市后的監(jiān)測報告表明,兒童發(fā)生肝損害的幾率比成人要低,在3%左右。建議治療期間至少每月監(jiān)測1次肝功能。如轉(zhuǎn)氨酶增高≤正常值高限3倍,可繼續(xù)用藥觀察；3～5倍之間,可將劑量減半或暫停用藥,每2周監(jiān)測1次肝功能,待轉(zhuǎn)氨酶恢復(fù)正常后再次使用；5～8倍之間,暫停用藥,每2周監(jiān)測1次肝功能,待轉(zhuǎn)氨酶恢復(fù)正常后可考慮再次用藥；但當(dāng)達8倍以上時,需立即停用,終生不再考慮重新用藥。 波生坦為非選擇性的雙重內(nèi)皮素受體拮抗劑,它不但與血管中的內(nèi)皮素受體A(ETA)結(jié)合,同時亦與腦、上皮細胞及平滑肌細胞中的內(nèi)皮素受體B(ETB)相結(jié)合。ET-1可競爭抑制ET1與ETA及ETB的結(jié)合,從而阻止ET-1強效的內(nèi)源性血管收縮作用和纖維化、致炎作用。目前國內(nèi)外針對特發(fā)性肺動脈高壓及缺氧、肺部炎癥等導(dǎo)致PAH報道較多,同時治療經(jīng)驗多針對成人及較大年齡組兒童,而針對嬰幼兒先天性心臟病合并肺動脈高壓的治療方面研究較少,尤其3個月以下小嬰兒先天性心臟病合并肺動脈高壓的治療方面更值得研究。 資料及方法： 病例選擇：選擇2012.01-2013.06在我院治療的3個月以下合并肺動脈高壓的先天性心臟病患者30例,所有患兒均經(jīng)過心電圖、胸部X光片、超聲心動圖檢查,確診為CHD合并肺動脈高壓。同時設(shè)年齡3個月以下健康小嬰兒10例,超聲心動圖檢查排除肺動脈高壓,為對照組。 分組：超聲心動圖確診CHD合并肺動脈高壓患兒按隨機數(shù)字法分成兩組： 波生坦組：在常規(guī)治療基礎(chǔ)上加用內(nèi)皮素受體拮抗劑波生坦口服的患兒作為治療組,具體方案：波生坦2mg/kg.次,每日兩次,療程7天；后改為4mg/kg.次,每日2次,療程3周,以后逐漸減量至停藥,總療程為8周。 卡托普利組：接受常規(guī)治療加卡托普利1mg/kg.d口服；常規(guī)治療包括：地高辛口服、安體舒通口服。 對照組：10例年齡3個月以下健康查體小嬰兒,超聲心動圖排除肺動脈高壓。 方法： 1、觀察組患兒均進行超聲心動圖檢查,估測肺動脈收縮壓≥60mm Hg,肺動脈平均壓≥45mm Hg,且心功能在紐約心臟病協(xié)會(NYHA)分級Ⅱ級以上。 2、三組患兒分別于入組前簽署知情同意書,實驗組患兒于治療前、治療后4周、8周分別抽取靜脈血2ml,檢測患兒肝功能、血小板及心肌酶譜變化；以觀察波生坦對患兒血小板、肝臟功能等的影響； 3、觀察組患兒治療前、治療后4周、8周及對照組患兒分別抽取靜脈血2ml,采用ELISA法測定患兒血漿ET-1水平；檢測波生坦對肺動脈高壓患兒血漿ET-1的影響； 4、觀察組患兒用藥前、用藥后4周及8周,超聲心動圖測定肺動脈收縮壓變化；通過30ml奶液喂養(yǎng)時間的變化進行患兒運動耐量評估。所記錄數(shù)據(jù)進行組間比較,以評價波生坦臨床治療效果。 統(tǒng)計學(xué)處理： 所有資料數(shù)據(jù)采用均數(shù)±標準差表示,采用SPSS17.0對所得結(jié)果進行統(tǒng)計學(xué)分析,P0.05為有統(tǒng)計學(xué)意義。 結(jié)果： 1.口服波生坦治療先天性心臟病相關(guān)PAH的患兒,經(jīng)治療后肺動脈收縮壓明顯降低。波生坦組患兒治療劑量2mg/kg.次,每日2次,口服4周及8周后進行心臟彩色超聲心動圖監(jiān)測,肺動脈收縮壓即有明顯改善,用藥后4周、用藥后8周與治療前比較差異均有顯著性意義(P0.001),由此說明波生坦可顯著降低PH患兒的平均肺動脈壓；卡托普利可使患兒的平均肺動脈壓下降,用藥后4周、用藥后8周與治療前比較差異有統(tǒng)計學(xué)意義(P0.05)。 2.經(jīng)過波生坦治療,患兒運動耐量能明顯得到改善。小嬰兒運動行為較少,目前尚無較為特效評估小嬰兒運動耐量的良好辦法,一般在吃奶時小嬰兒可以精力集中,故測量患兒1次完成30ml奶液(嬰幼兒配方奶及母乳)的喂養(yǎng)時間,可作為評估患兒運動耐量方便、可行,且較為準確的衡量標準�？诜ㄉ�(內(nèi)皮素受體拮抗劑)治療,可使患兒30ml奶液的喂養(yǎng)時間明顯縮短,治療4周后,喂養(yǎng)時間由原來的平均20.55min降為16.05min,有顯著意義(P0.01)。 3.肺動脈高壓時,血漿ET-1水平升高,表明肺動脈壓力升高時,血管內(nèi)皮細胞合成和釋放增加,與對照組相比,有顯著差異(P0.05)。波生坦組用藥后4周、用藥后8周與治療前比較差異均有顯著性意義(P0.01),由此可見,波生坦可顯著降低血漿ET-1水平(P0.01)；卡托普利可使兒血漿E T-1水平下降,但用藥后4周及8周與治療前比較差異均無顯著性意義(P0.05)。 4.本實驗在短期、小劑量口服波生坦治療的過程中,未見有不良反應(yīng)的發(fā)生,患兒耐受性好�？诜委�4周及8周后,復(fù)查患兒肝功能均在正常范圍。 結(jié)論： 1.先心病肺動脈高壓患兒血漿ET-1水平與對照組比較明顯升高,表明當(dāng)肺動脈壓力升高時,血管內(nèi)皮細胞合成及釋放ET-1增加。 2.本研究首次在小于3個月的嬰兒應(yīng)用波生坦,且波生坦與卡托普利比較可更明顯降低先天性心臟病相關(guān)PAH患兒肺動脈壓力。 3.波生坦能顯著改善先天性心臟病相關(guān)PAH患兒的心臟功能,提高運動耐量。 4.短期、小劑量口服波生坦治療小嬰兒先天性心臟病合并肺動脈高壓,患兒肝腎功能無明顯異常。證實波生坦治療小嬰兒肺動脈高壓安全、有效。
[Abstract]:Background of Study :

Pulmonary arterial hypertension is a common and serious complication of congenital heart disease ( left - to - right shunt ) . It is a serious threat to the life of children . The risk and mortality rate of patients with severe pulmonary hypertension are significantly increased . There is a lack of special treatment methods at present . Therefore , it is necessary to study the treatment of pulmonary hypertension .

Endothelin - 1 ( ET - 1 ) is one of the most potent vasoconstrictors in patients with congenital heart disease . ET - 1 is a potent endogenous vasomotor and mitogen . ET - 1 is one of the important causes of PAH . In recent years , it has been found that the level of ET - 1 mRNA in pulmonary tissues of patients with congenital heart disease ( CHD ) increased significantly in patients with congenital heart disease . ET - 1 is combined with endothelin receptor A ( ETA ) and B ( ETB ) on the surface of smooth muscle cells .

For the first time , Bosentan was the first non - control open BREATHE - 3 study approved for PAH , which was first confirmed to be safe for use in the treatment of children ' s PAH and significantly improved the hemodynamic parameters of patients with PAH . In July 2009 , the initial dose recommended was 2 mg / kg bid . The currently ongoing study was intended to evaluate the pharmacokinetics , tolerability , safety and efficacy of 3 patients with PAH for 3 months to 12 years , and the preliminary results were encouraging .

The most common side effects of bosentan are the elevation of transaminase due mainly to the competitive inhibition of bile salt transport , but there has been no permanent liver function damage . The monitoring report after Posetin ' s marketing shows that the incidence of liver damage in children is lower than that of adults , and is about 3 % . It is suggested that the liver function should be monitored at least once a month during the treatment period . For example , the elevation of transaminase is 3 times higher than the normal value , and the observation of medication can be continued ;
between 3 and 5 times , the dosage can be reduced by half or the medicine is paused , and once every 2 weeks , the liver function is monitored , and after the transaminase returns to normal , the medicine is used again ;
between 5 and 8 times , the medicine is suspended , the liver function is monitored once every two weeks , and after the transaminase is returned to normal , the medicine can be taken into account again ;
However , when up to 8 times , the product is stopped immediately , and the life - life is no longer considered for re - use .

Bosentan is a non - selective double endothelin receptor antagonist , which binds not only to endothelin receptor A ( ETA ) in blood vessels but also to endothelin receptor B ( ETB ) in brain , epithelial cells and smooth muscle cells .

Materials and Methods :

Case Selection : Select 30 cases of congenital heart disease with pulmonary hypertension after 3 months of treatment in our hospital in 2012 . 01 - 2013.06 . All the children were diagnosed as CHD with pulmonary hypertension by electrocardiogram , chest X - ray and echocardiography .

Group : Echocardiography was divided into two groups according to the random number method for children with CHD combined with pulmonary hypertension .

Posentan group : The treatment group was treated on the basis of routine therapy with endothelin receptor antagonist bosentan as the treatment group , and the specific protocol was as follows : bosentan 2mg / kg . times , twice daily , duration of treatment for 7 days ;
The treatment course was 4 mg / kg once a day , twice a day , 3 weeks in treatment course , and then gradually reduced to drug withdrawal , and the total course of treatment was 8 weeks .

captopril group : conventional therapy plus captopril 1mg / kg 路 d oral administration ;
Routine therapy includes : digoxin oral administration , oxintong oral administration .

Control group : 10 small infants with 3 months of age were examined by echocardiography to exclude pulmonary hypertension .

Method :

1 . All patients in the observation group were examined by echocardiography to estimate the pulmonary artery systolic pressure 鈮，

本文編號：1899140